Laxmikeshav Kritika, Sayali Mone, Devabattula Geetanjali, Valapil Durgesh G, Mahale Ashutosh, Sharma Pravesh, George Joel, Phanindranath Regur, Godugu Chandraiah, Kulkarni Onkar P, Nagesh Narayana, Shankaraiah Nagula
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India.
Department of Biological Sciences (Regulatory Toxicology), National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India.
Arch Pharm (Weinheim). 2023 May;356(5):e2200449. doi: 10.1002/ardp.202200449. Epub 2023 Feb 17.
A simple "click" protocol was employed in the quest of synthesizing 1,2,3-triazole-linked benzimidazoles as promising anticancer agents on various human cancer cell lines such as A549, HCT116, SK-Mel-28, HT-29, and MCF-7. Compound 12j demonstrated significant cytotoxic potential towards SK-Mel-28 cancer cells (IC : 4.17 ± 0.09 µM) and displayed no cytotoxicity (IC : > 100 µM) against normal human BEAS-2B cells inferring its safety towards normal healthy cells. Further to comprehend the underlying apoptosis mechanisms, AO/EB, dichlorodihydrofluorescein diacetate (DCFDA), and 4',6-diamidino-2-phenylindole (DAPI) staining were performed, which revealed the nuclear and morphological alterations. Compound 12j displayed impairment in cellular migration and inhibited colony formation. The annexin V binding assay and JC-1 were implemented to evaluate the scope of apoptosis and the loss of the mitochondrial transmembrane potential in SK-Mel-28 cells. Cell-cycle analysis revealed that compound 12j arrested the cells at the G2/M phase in a dose-dependent manner. Target-based assays established the inhibition of tubulin polymerization by 12j at an IC value of 5.65 ± 0.05 μM and its effective binding with circulating tumor DNA as a DNA intercalator. The detailed binding interactions of 12j with tubulin and DNA were examined by docking studies on PDB ID: 3E22 and DNA hexamer (PDB ID: 1NAB), respectively.
采用一种简单的“点击”方案来合成1,2,3-三唑连接的苯并咪唑，将其作为有前景的抗癌剂，用于多种人类癌细胞系，如A549、HCT116、SK-Mel-28、HT-29和MCF-7。化合物12j对SK-Mel-28癌细胞显示出显著的细胞毒性潜力（IC₅₀：4.17±0.09 μM），而对正常人BEAS-2B细胞无细胞毒性（IC₅₀：>100 μM），这表明其对正常健康细胞具有安全性。为了进一步理解潜在的凋亡机制，进行了吖啶橙/溴化乙锭（AO/EB）、二氯二氢荧光素二乙酸酯（DCFDA）和4',6-二脒基-2-苯基吲哚（DAPI）染色，结果揭示了细胞核和形态学变化。化合物12j表现出细胞迁移受损并抑制集落形成。采用膜联蛋白V结合试验和JC-1来评估SK-Mel-28细胞中的凋亡范围和线粒体跨膜电位的丧失。细胞周期分析表明，化合物12j以剂量依赖性方式使细胞停滞在G2/M期。基于靶点的试验确定化合物12j在IC₅₀值为5.65±0.05 μM时抑制微管蛋白聚合，并作为DNA嵌入剂与循环肿瘤DNA有效结合。分别通过对PDB ID：3E22上的微管蛋白和DNA六聚体（PDB ID：1NAB）进行对接研究，考察了化合物12j与微管蛋白和DNA的详细结合相互作用。
